This invention relates to a new and useful process for preparing a known ketimine compound. More particularly, it is concerned with an improved method for preparing N-[4-(3,4-dichlorphenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine, which is known to be of value as a key intermediate in the production of the antidepressant agent known as cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthal enamine (sertraline).
In the past, N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine has been obtained by condensing 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone with methylamine in the presence of titanium tetrachloride in accordance with the method described by W. R. Welch, Jr. et al. in U.S. Pat. No. 4,536,518, as well as in the paper of the same authors appearing in the Journal of Medicinal Chemistry Vol. 27, No. 11, p. 1508 (1984). However this, method involves the use of certain stringent safety requirements that are called for in connection with the handling of titanium tetrachloride (necessitated by the fact that this reagent is extremely reactive with water) and the use of various hazardous waste disposal techniques that are required for the removal of the titanium tetrachloride by-products of the condensation reaction (viz., titanium dioxide and methylamine hydrochloride). In the search for newer and more improved methods of production in this particular area, little is known about the use of other dehydrating agents, such as molecular sieves, etc., with the naphthalenone ring system in this type condensation reaction even though these agents have been employed in the past with variable success in the field of condensation chemistry (i.e., ketimine synthesis) with respect to other ketone substrates. For instance, E. P. Kyba in Organic Preparations and Procedures, Vol. 2(2), p. 149 (1970) discloses the use of molecular sieves to prepare several ketimines derived from various methyl ketones and methylamine, while K. Taguchi et al, in the Journal of Organic Chemistry, Vol. 36, p. 1570 (1971) extends this work to certain hindered ketones and further reports on the catalytic effects of molecular sieves in the formation of ketimines derived from medium-sized ring ketones and aromatic amines such as aniline and m-toluidine.